Understanding the functional role of Myeloid Derived Suppressor cells in tuberculosis

项目摘要。结核分枝杆菌（Mtb），疾病的病原体 据估计，结核病（TB）感染了世界四分之一的人口， 1.6每年死亡百万人。多重耐药和广泛耐药结核分枝杆菌菌株的出现 以及目前使用的疫苗M.牛卡介苗（BCG）， 全球结核病控制的障碍。因此，迫切需要更好地了解 结核病免疫发病机制，因为这种机制可以有针对性地改善宿主对结核分枝杆菌的控制 感染结核肉芽肿长期以来被认为是结核病的标志。我们公布的数据 提示含有诱导型支气管相关淋巴组织（iBALT）的存在， 肉芽肿指示在TB潜伏期期间介导Mtb控制的保护性肉芽肿。在 相反，浸润性髓源性抑制细胞（MDSC）以及中性粒细胞产生 促炎分子是肺结核期间非保护性肉芽肿的特征。 MDSC在人、非人灵长类动物（NHP）和小鼠的肺TB期间被诱导， 抑制保护性T细胞反应。我们的新数据显示，促炎因子 细胞因子，白细胞介素（IL）-17在抑制肺MDSC积聚和限制T细胞抑制中的作用 在肺结核病期间。此外，我们发现MDSC衍生的促炎蛋白， S100 A8/A9异二聚体在人、NHP和小鼠中Mtb感染后被诱导。此外，委员会认为， 表达S100 A8/A9的髓样细胞在结核肉芽肿内积聚并扩大肺 MDSC蓄积介导Mtb易感性。在目前的提案中，使用鼠标和NHP 结核病模型，我们将阐明调节和促进MDSC积累的机制 在TB期间，并表征MDSC及其途径是否可以作为宿主定向靶向 治疗结核病的药物（HDTs）。在具体目标1中，使用基因缺陷和条件基因缺陷 小鼠模型，我们将确定IL-17依赖性途径，限制MDSC的积累， TB.在具体目标2中，我们将评估S100 A8/A9蛋白在驱动MDSC蓄积中的作用。 以及对TB的敏感性，并且还确定阻塞S100 A8/A9信令是否将限制TB 复发最后，在具体目标3中，我们将评估MDSC耗竭是否可以预防结核病进展， 非人灵长类动物（NHP）。在完成这里提出的目标时，我们将有相当大的 扩大了我们对结核分枝杆菌特异性信号通路的理解， （S100 A8/A9途径）和负（IL-17依赖性途径）调节MDSC蓄积 肺结核期间。此外，我们在NHP中的转化研究将使HDT的使用能够限制MDSC 肺结核期间。

PROJECT SUMMARY. Mycobacterium tuberculosis (Mtb), the causative agent of the disease tuberculosis (TB), is estimated to infect one-fourth of the world's population, resulting in approximately 1.6 million deaths each year. The emergence of multidrug- and extensively drug-resistant Mtb strains and the variable efficacy of the currently used vaccine, M. bovis Bacille Calmette Guerin (BCG), are barriers to the global control of TB. Thus, there is a critical need to better understand the mechanisms of TB immunopathogenesis, as such mechanisms can be targeted to improve host control of Mtb infection. The tubercle granuloma is long been considered a hallmark of TB. Our published data suggest that the presence of inducible bronchus-associated lymphoid tissue (iBALT)-containing granulomas is indicative of protective granulomas that mediate Mtb control during TB latency. In contrast, infiltrating myeloid derived suppressor cells (MDSCs) as well as neutrophils producing proinflammatory molecules are characteristic of non-protective granulomas during pulmonary TB. MDSCs are induced during pulmonary TB in humans, nonhuman primates (NHPs) and mice and suppress protective T cell responses. Our new data show a protective role for the proinflammatory cytokine, Interleukin (IL)-17 in dampening lung MDSC accumulation and limiting T cell suppression in the lung during TB. Additionally, we show that the MDSC-derived proinflammatory proteins, S100A8/A9 heterodimers are induced upon Mtb infection in humans, NHPs and mice. Furthermore, S100A8/A9-expressing myeloid cells accumulate within the tubercle granuloma and amplify lung MDSC accumulation to mediate Mtb susceptibility. In the current proposal, using mouse and NHP models of TB, we will elucidate the mechanism(s) which regulate and promote MDSC accumulation during TB, and characterize whether MDSCs and their pathways can be targeted as host-directed therapeutics (HDTs) for TB. In Specific Aim 1, using gene deficient and conditional gene deficient mouse models we will determine the IL-17-dependent pathways that limit MDSC accumulation during TB. In Specific Aim 2, we will evaluate the role of S100A8/A9 proteins in driving MDSC accumulation and susceptibility to TB, and also determine whether blocking S100A8/A9 signaling will limit TB relapse. Finally, in Specific Aim 3 we will evaluate if MDSC depletion can prevent TB progression in nonhuman primates (NHPs). At the completion of the aims proposed here, we will have considerably expanded our understanding of the Mtb-specific signaling pathways and factors that positively (S100A8/A9 pathways) and negatively (IL-17 dependent pathways) regulate MDSC accumulation during TB. Additionally, our translational studies in NHPs will enable the use of HDTs to limit MDSCs during TB.